PROJECT SUMMARY/ABSTRACT MAIN RESEARCH COMPONENT 4 Alcohol is one of the most widely used substances by American adolescents, with binge and heavy drinking evident in almost two thirds of underage current drinkers. These high rates of binge and heavy drinking are alarming, since adolescents who engage in even episodic heavy drinking are more likely to exhibit alcohol use disorders and other adverse consequences later in life. Young people predominantly drink in social situations, although this context specificity ? let alone sex differences in sensitivity to social consequences ? has been little investigated. Using a rat model of adolescence, we have shown pronounced qualitative sex differences in the precursors and effects of ethanol contributing to high social drinking among adolescents. High social drinking among males is associated with high social activity and enhanced sensitivity to the socially facilitating effects of ethanol, whereas in adolescent females, higher levels of social drinking are associated with elevated social anxiety and enhanced sensitivity to the socially anxiolytic effects of ethanol. The present proposal is designed to separately determine brain regions that are responsible for high social activity and sensitivity to ethanol-induced social facilitation in adolescent males, in contrast to regions related to high social anxiety and enhanced sensitivity to the socially anxiolytic effects of ethanol in females. Target brain regions that are differentially activated in males and females with high social drinking phenotypes will be determined using transgenic cFos-LacZ rats and X-Gal staining for c-Fos. The Daun02 procedure will then be used to selectively inactivate neuronal ensembles in specified target regions that were activated by the social stimulus alone or in combination with acute EtOH, and consequences of this inactivation on subsequent social drinking determined in male and female high social drinkers. We expect that inactivation of neural ensembles activated by social interactions alone or in combination with acute EtOH in high socially active males will attenuate social drinking in these animals, whereas inactivation of neuronal ensembles activated in high socially anxious adolescent females by social stimuli will diminish social drinking in these females. Given the critical importance of brain vasopressin/oxytocin peptide systems in regulation of social behavior and social anxiety, we will also test the hypothesis that high social drinking in males is associated with hyperactivity of the brain vasopressin V1a receptor, whereas functional hypoactivity of the brain oxytocin system contributes to high social drinking in adolescent females. These hypotheses will be tested neuropharmacologically and via assessment of protein levels for oxytocin and vasopressin and their receptors in the brain regions sex-specifically associated with high drinking phenotypes. The work outlined in this proposal will be among the first to examine neural contributors to the pronounced qualitative sex differences in precursors leading to high social drinking among adolescents, and are essential for creation of new, sex-specific early prevention and intervention strategies for heavy alcohol use in adolescence.